Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Signal integration by JNK and p38 MAPK pathways in cancer development

Key Points

  • Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs) have important roles in the signalling mechanisms that orchestrate cellular responses to many types of stresses, but also control the proliferation, differentiation, survival and migration of specific cell types.

  • JNKs and p38 MAPKs can exert antagonistic effects on cell proliferation and survival, which depend on cell type-specific differences, as well as on the intensity and duration of the signal and the crosstalk between other signalling pathways.

  • Crosstalk between the JNK and p38 MAPK pathways is emerging as an important regulatory mechanism in many cellular responses.

  • The JNK and p38 MAPK pathways regulate the activity and expression of key inflammatory mediators, including cytokines and proteases, which may function as potent cancer promoters.

  • The specific role of individual JNK and p38 MAPK family members in particular cellular processes in vivo has been addressed by gene-targeting experiments in mice. Genetically engineered mouse models have confirmed the importance of these pathways for tumorigenesis in various organs.

  • The expression or activity of JNK and p38 MAPK pathway components is often altered in human tumours and cancer cell lines. Given the many tumorigenesis-related functions that these kinases can control, both in the cancer cell and in the tumour microenvironment, it is important to carefully consider the type of tumour before attempting to modulate these pathways for cancer therapy.

Abstract

Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members function in a cell context-specific and cell type-specific manner to integrate signals that affect proliferation, differentiation, survival and migration. Consistent with the importance of these events in tumorigenesis, JNK and p38 MAPK signalling is associated with cancers in humans and mice. Studies in mouse models have been essential to better understand how these MAPKs control cancer development, and these models are expected to provide new strategies for the design of improved therapeutic approaches. In this Review we highlight the recent progress made in defining the functions of the JNK and p38 MAPK pathways in different cancers.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Activation of mitogen-activated protein kinase signalling pathways.
Figure 2: Signal integration between Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs).

Similar content being viewed by others

References

  1. Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Rev. Cancer 4, 937–947 (2004).

    Article  CAS  Google Scholar 

  2. Nebreda, A. R. & Porras, A. p38 MAP kinases: beyond the stress response. Trends Biochem. Sci. 25, 257–260 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Kyriakis, J. M. & Avruch, J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807–869 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Karin, M. & Gallagher, E. From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life 57, 283–295 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Weston, C. R. & Davis, R. J. The JNK signal transduction pathway. Curr. Opin. Cell Biol. 19, 142–149 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Rincon, M. & Davis, R. J. Regulation of the immune response by stress-activated protein kinases. Immunol. Rev. 228, 212–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Morrison, D. K. & Davis, R. J. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. Biol. 19, 91–118 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Avruch, J. MAP kinase pathways: the first twenty years. Biochim. Biophys. Acta. 1773, 1150–1160 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Gupta, S. et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15, 2760–2770 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cuevas, B. D., Abell, A. N. & Johnson, G. L. Role of mitogen-activated protein kinase kinase kinases in signal integration. Oncogene 26, 3159–3171 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Bode, A. M. & Dong, Z. The functional contrariety of JNK. Mol. Carcinog. 46, 591–598 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nature Rev. Cancer 3, 859–868 (2003).

    Article  CAS  Google Scholar 

  14. Altucci, L. & Gronemeyer, H. The promise of retinoids to fight against cancer. Nature Rev. Cancer 1, 181–193 (2001).

    Article  CAS  Google Scholar 

  15. Lee, J. C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Sanz, V., Arozarena, I. & Crespo, P. Distinct carboxy-termini confer divergent characteristics to the mitogen-activated protein kinase p38α and its splice isoform Mxi2. FEBS Lett. 474, 169–174 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Ono, K. & Han, J. The p38 signal transduction pathway: activation and function. Cell Signal 12, 1–13 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Cuenda, A. & Rousseau, S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta 1773, 1358–1375 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Mittelstadt, P. R., Salvador, J. M., Fornace, A. J. Jr & Ashwell, J. D. Activating p38 MAPK: new tricks for an old kinase. Cell Cycle 4, 1189–1192 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Bulavin, D. V. & Fornace, A. J. Jr. p38 MAP kinase's emerging role as a tumor suppressor. Adv. Cancer Res. 92, 95–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Dolado, I. & Nebreda, A. R. Regulation of tumorigenesis by p38αMAP kinase. Topics in Current Genetics: Stress-Activated Protein Kinases 20, 99–128 (2008).

    Article  CAS  Google Scholar 

  22. Hui, L., Bakiri, L., Stepniak, E. & Wagner, E. F. p38a: a suppressor of cell proliferation and tumorigenesis. Cell Cycle 6, 2429–2433 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Sabapathy, K. et al. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol. Cell 15, 713–725 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Sabapathy, K. & Wagner, E. F. JNK2: a negative regulator of cellular proliferation. Cell Cycle 3, 1520–1523 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Fuchs, S. Y., Dolan, L., Davis, R. J. & Ronai, Z. Phosphorylation-dependent targeting of c-Jun ubiquitination by Jun N-kinase. Oncogene 13, 1531–1535 (1996).

    CAS  PubMed  Google Scholar 

  26. Jaeschke, A. et al. JNK2 is a positive regulator of the cJun transcription factor. Mol. Cell 23, 899–911 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Das, M. et al. Suppression of p53-dependent senescence by the JNK signal transduction pathway. Proc. Natl Acad. Sci. USA 104, 15759–15764 (2007). This paper links the JNK pathway to p53-dependent senescence using a conditional

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tournier, C. et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288, 870–874 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Hochedlinger, K., Wagner, E. F. & Sabapathy, K. Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis. Oncogene 21, 2441–2445 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Ventura, J. J. et al. Chemical genetic analysis of the time course of signal transduction by JNK. Mol. Cell 21, 701–710 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Chang, L. et al. The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. Cell 124, 601–613 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Deng, Y., Ren, X., Yang, L., Lin, Y. & Wu, X. A JNK-dependent pathway is required for TNFα-induced apoptosis. Cell 115, 61–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Huang, C., Rajfur, Z., Borchers, C., Schaller, M. D. & Jacobson, K. JNK phosphorylates paxillin and regulates cell migration. Nature 424, 219–223 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. David, J. P., Sabapathy, K., Hoffmann, O., Idarraga, M. H. & Wagner, E. F. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J. Cell Sci. 115, 4317–4325 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Rincon, M. et al. The JNK pathway regulates the in vivo deletion of immature CD4+CD8+thymocytes. J. Exp. Med. 188, 1817–1830 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ambrosino, C. & Nebreda, A. R. Cell cycle regulation by p38 MAP kinases. Biol. Cell 93, 47–51 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Thornton, T. M. & Rincon, M. Non-classical p38 MAP kinase functions: cell cycle checkpoints and survival. Int. J. Biol. Sci. 5, 44–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, X. et al. Involvement of the MKK6–p38γ cascade in γ-radiation-induced cell cycle arrest. Mol. Cell Biol. 20, 4543–4552 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Han, J. & Sun, P. The pathways to tumor suppression via route p38. Trends Biochem. Sci. 32, 364–371 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Engel, F. B. et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 19, 1175–1187 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hui, L. et al. p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway. Nature Genet. 39, 741–749 (2007). Genetically engineered mouse models show that p38α negatively regulates the proliferation of hepatocytes, fibroblasts and haematopoietic cells, as well as liver tumorigenesis. Downregulation of the JNK/JUN pathway has an important role in these effects of p38α.

    Article  CAS  PubMed  Google Scholar 

  43. Ventura, J. J. et al. p38α MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nature Genet. 39, 750–758 (2007). This paper provides genetic evidence for the role of p38α in coordinating proliferation and differentiation of lung epithelial cells. As a consequence, p38α-deficient mice are highly sensitized to Kras -induced lung tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  44. Schindler, E. M. et al. p38δ Mitogen-activated protein kinase is essential for skin tumor development in mice. Cancer Res. 69, 4648–4655 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Platanias, L. C. MAP kinase signaling pathways and hematologic malignancies. Blood 101, 4667–4679 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, R. J. et al. pp60(v-src) induction of cyclin D1 requires collaborative interactions between the extracellular signal-regulated kinase, p38, and Jun kinase pathways. A role for cAMP response element-binding protein and activating transcription factor-2 in pp60(v-src) signaling in breast cancer cells. J. Biol. Chem. 274, 7341–7350 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Halawani, D., Mondeh, R., Stanton, L. A. & Beier, F. p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation. Oncogene 23, 3726–3731 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Ricote, M. et al. The p38 transduction pathway in prostatic neoplasia. J. Pathol. 208, 401–407 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Recio, J. A. & Merlino, G. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Oncogene 21, 1000–1008 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Fan, L. et al. A novel role of p38α MAPK in mitotic progression independent of its kinase activity. Cell Cycle 4, 1616–1624 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Neve, R. M., Holbro, T. & Hynes, N. E. Distinct roles for phosphoinositide 3-kinase, mitogen-activated protein kinase and p38 MAPK in mediating cell cycle progression of breast cancer cells. Oncogene 21, 4567–4576 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Dolado, I. et al. p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell 11, 191–205 (2007). This paper shows that p38α negatively regulates the initiation of tumorigenesis by sensing the oncogene-induced accumulation of reactive oxygen species and triggering apoptosis.

    Article  CAS  PubMed  Google Scholar 

  53. Kaiser, R. A. et al. Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J. Biol. Chem. 279, 15524–15530 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Nemoto, S., Xiang, J., Huang, S. & Lin, A. Induction of apoptosis by SB202190 through inhibition of p38β mitogen-activated protein kinase. J. Biol. Chem. 273, 16415–16420 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Silva, G., Cunha, A., Gregoire, I. P., Seldon, M. P. & Soares, M. P. The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38α MAPK isoform. J. Immunol. 177, 1894–1903 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nature Rev. Cancer 7, 834–846 (2007).

    Article  CAS  Google Scholar 

  57. Comes, F. et al. A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells. Cell Death Differ. 14, 693–702 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Thornton, T. M. et al. Phosphorylation by p38 MAPK as an alternative pathway for GSK3β inactivation. Science 320, 667–670 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Aouadi, M. et al. p38 mitogen-activated protein kinase activity commits embryonic stem cells to either neurogenesis or cardiomyogenesis. Stem Cells 24, 1399–1406 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Schmelter, M., Ateghang, B., Helmig, S., Wartenberg, M. & Sauer, H. Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation. FASEB J. 20, 1182–1184 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Lluis, F., Perdiguero, E., Nebreda, A. R. & Muñoz-Canoves, P. Regulation of skeletal muscle gene expression by p38 MAP kinases. Trends Cell Biol. 16, 36–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Perdiguero, E. & Muñoz-Canoves, P. Transcriptional regulation by the p38 MAPK signalling pathway in mammalian cells. Topics in Current Genetics: Stress-Activated Protein Kinases 20, 51–79 (2008).

    Article  CAS  Google Scholar 

  63. Forte, G. et al. Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells 24, 23–33 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Perdiguero, E. et al. Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38α in abrogating myoblast proliferation. EMBO J. 26, 1245–1256 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Puri, P. L. et al. Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. Genes Dev. 14, 574–584 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Finn, G. J., Creaven, B. S. & Egan, D. A. Daphnetin induced differentiation of human renal carcinoma cells and its mediation by p38 mitogen-activated protein kinase. Biochem. Pharmacol. 67, 1779–1788 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Ordonez-Moran, P. et al. RhoA–ROCK and p38MAPK–MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. J. Cell Biol. 183, 697–710 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hazzalin, C. A. et al. p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient. Curr. Biol. 6, 1028–1031 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Nemoto, S., Sheng, Z. & Lin, A. Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy. Mol. Cell Biol. 18, 3518–3526 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tourian, L. Jr, Zhao, H. & Srikant, C. B. p38α, but not p38β, inhibits the phosphorylation and presence of c-FLIPS in DISC to potentiate Fas-mediated caspase-8 activation and type I apoptotic signaling. J. Cell Sci. 117, 6459–6471 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Wada, T. et al. Antagonistic control of cell fates by JNK and p38-MAPK signaling. Cell Death Differ. 15, 89–93 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Cheung, P. C., Campbell, D. G., Nebreda, A. R. & Cohen, P. Feedback control of the protein kinase TAK1 by SAPK2a/p38α. EMBO J. 22, 5793–5805 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Muniyappa, H. & Das, K. C. Activation of c-Jun N.-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK3–MKK7-dependent mechanism. Cell Signal 20, 675–683 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Stepniak, E. et al. c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev. 20, 2306–2314 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Heinrichsdorff, J., Luedde, T., Perdiguero, E., Nebreda, A. R. & Pasparakis, M. p38α MAPK inhibits JNK activation and collaborates with IκB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep. 9, 1048–1054 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kamata, H. et al. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649–661 (2005). The paper shows that hepatocytes lacking IKKβ show reduced JNK phosphatase activity, leading to sustained JNK1 activation and increased liver carcinogenesis.

    Article  CAS  PubMed  Google Scholar 

  77. Papa, S. et al. Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. Nature Cell Biol. 6, 146–153 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Papa, S. et al. Gadd45β promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J. Clin. Invest. 118, 1911–1923 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Maeda, S. et al. IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα. Immunity 19, 725–737 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Hasselblatt, P., Rath, M., Komnenovic, V., Zatloukal, K. & Wagner, E. F. Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 17105–17110 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005). References 81–83 clearly show that the JNK pathway induces cell death in Con A-induced hepatitis and cytokine-driven hepatocarcinogenesis, whereas JUN/AP1 is hepatoprotective in the Con A model of hepatitis and antagonizes JNK function.

    Article  CAS  PubMed  Google Scholar 

  84. Das, M. et al. Induction of hepatitis by JNK-mediated expression of TNF-α. Cell 136, 249–260 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hammaker, D. R., Boyle, D. L., Inoue, T. & Firestein, G. S. Regulation of the JNK pathway by TGF-β activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res. Ther. 9, R57 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Ricci, R. et al. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science 306, 1558–1561 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Bachelor, M. A. & Bowden, G. T. UVA-mediated activation of signaling pathways involved in skin tumor promotion and progression. Semin. Cancer Biol. 14, 131–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Timoshenko, A. V., Chakraborty, C., Wagner, G. F. & Lala, P. K. COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br. J. Cancer 94, 1154–1163 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Xu, K. & Shu, H. K. EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas. Cancer Res. 67, 6121–6129 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Kumar, S., Boehm, J. & Lee, J. C. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nature Rev. Drug Discov. 2, 717–726 (2003).

    Article  CAS  Google Scholar 

  92. Clark, A. R., Dean, J. L. & Saklatvala, J. Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett. 546, 37–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Kim, C. et al. The kinase p38α serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nature Immunol. 9, 1019–1027 (2008).

    Article  CAS  Google Scholar 

  94. Kang, Y. J. et al. Macrophage deletion of p38α partially impairs lipopolysaccharide-induced cellular activation. J. Immunol. 180, 5075–5082 (2008). References 93 and 94 provide genetic evidence for the regulation of cytokine production and inflammatory responses by p38α in myeloid and epithelial cells.

    Article  CAS  PubMed  Google Scholar 

  95. Beardmore, V. A. et al. Generation and characterization of p38β (MAPK11) gene-targeted mice. Mol. Cell. Biol. 25, 10454–10464 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. O'Keefe, S. J. et al. Chemical genetics define the roles of p38α and p38β in acute and chronic inflammation. J. Biol. Chem. 282, 34663–34671 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Emerling, B. M. et al. Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling. Mol. Cell Biol. 25, 4853–4862 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hsieh, Y. H. et al. p38 mitogen-activated protein kinase pathway is involved in protein kinase Cα-regulated invasion in human hepatocellular carcinoma cells. Cancer Res. 67, 4320–4327 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Junttila, M. R. et al. p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 26, 5267–5279 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Demuth, T. et al. MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival. Mol. Cancer Ther. 6, 1212–1222 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Matsuo, Y. et al. Involvement of p38α mitogen-activated protein kinase in lung metastasis of tumor cells. J. Biol. Chem. 281, 36767–36775 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Loesch, M. & Chen, G. The p38 MAPK stress pathway as a tumor suppressor or more? Front. Biosci. 13, 3581–3593 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hickson, J. A. et al. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 66, 2264–2270 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Vander Griend, D. J. et al. Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res. 65, 10984–10991 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Kim, M. S., Lee, E. J., Kim, H. R. & Moon, A. p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res. 63, 5454–5461 (2003).

    CAS  PubMed  Google Scholar 

  106. Dreissigacker, U. et al. Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38. Cell Signal. 18, 1156–1168 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. McMullen, M. E., Bryant, P. W., Glembotski, C. C., Vincent, P. A. & Pumiglia, K. M. Activation of p38 has opposing effects on the proliferation and migration of endothelial cells. J. Biol. Chem. 280, 20995–21003 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Rousseau, S. et al. CXCL12 and C5a trigger cell migration via a PAK1/2–p38α MAPK–MAPKAP–K2–HSP27 pathway. Cell Signal 18, 1897–1905 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biol. 8, 1369–1375 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Kobayashi, M., Nishita, M., Mishima, T., Ohashi, K. & Mizuno, K. MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration. EMBO J. 25, 713–726 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Eferl, R. et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112, 181–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Sakurai, T., Maeda, S., Chang, L. & Karin, M. Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl Acad. Sci. USA 103, 10544–10551 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hui, L., Zatloukal, K., Scheuch, H., Stepniak, E. & Wagner, E. F. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J. Clin. Invest. 118, 3943–3953 (2008). References 112 and 113 describe the molecular functions of JNK1 and JNK2 in mouse and human liver cancer cells using mouse liver carcinogenesis models and human liver cancer cell lines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen, F. & Castranova, V. Beyond apoptosis of JNK1 in liver cancer. Cell Cycle 8, 1145–1147 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. She, Q. B., Chen, N., Bode, A. M., Flavell, R. A. & Dong, Z. Deficiency of c-Jun-NH2-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 62, 1343–1348 (2002).

    CAS  PubMed  Google Scholar 

  116. Chen, N. et al. Suppression of skin tumorigenesis in c-Jun NH2-terminal kinase-2-deficient mice. Cancer Res. 61, 3908–3912 (2001).

    CAS  PubMed  Google Scholar 

  117. Nateri, A. S., Spencer-Dene, B. & Behrens, A. Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437, 281–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Sancho, R. et al. JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J. (2009).

  119. Hasselblatt, P., Gresh, L., Kudo, H., Guinea-Viniegra, J. & Wagner, E. F. The role of the transcription factor AP-1 in colitis-associated and beta-catenin-dependent intestinal tumorigenesis in mice. Oncogene 27, 6102–6109 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Tong, C. et al. c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. Am. J. Pathol. 171, 297–303 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Shibata, W. et al. c-Jun NH2-terminal kinase 1 is a critical regulator for the development of gastric cancer in mice. Cancer Res. 68, 5031–5039 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Hess, P., Pihan, G., Sawyers, C. L., Flavell, R. A. & Davis, R. J. Survival signaling mediated by c-Jun NH2-terminal kinase in transformed B lymphoblasts. Nature Genet. 32, 201–205 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Bulavin, D. V. et al. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nature Genet. 31, 210–215 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Brancho, D. et al. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 17, 1969–1978 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bulavin, D. V. et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16Ink4a–p19Arf pathway. Nature Genet. 36, 343–350 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Demidov, O. N. et al. The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene 26, 2502–2506 (2007). References 125 and 126 provide in vivo evidence for the role of PPM1D, a negative regulator of p38α, in mammary gland tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  127. Tront, J. S., Hoffman, B. & Liebermann, D. A. Gadd45a suppresses Ras-driven mammary tumorigenesis by activation of c-Jun NH2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence. Cancer Res. 66, 8448–8454 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Yang, Y. A., Zhang, G. M., Feigenbaum, L. & Zhang, Y. E. Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2. Cancer Cell 9, 445–457 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Breitwieser, W. et al. Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. Genes Dev. 21, 2069–2082 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008). This paper shows that p38α may indirectly control liver carcinogenesis by suppressing hepatocyte necrosis and the release of IL-1α.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sun, P. et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295–308 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Shi, Y. et al. Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination. Mol. Cell. Biol. 23, 7732–7741 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Whitmarsh, A. J. & Davis, R. J. Role of mitogen-activated protein kinase kinase 4 in cancer. Oncogene 26, 3172–3184 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Johnson, G. L. & Nakamura, K. The c-jun kinase/stress-activated pathway: Regulation, function and role in human disease. Biochim. et Biophys. Acta 1773, 1341–1348 (2007).

    Article  CAS  Google Scholar 

  135. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chang, Q. et al. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J. Hepatol. 50, 323–333 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Yoshida, S. et al. The c-Jun NH2-terminal kinase 3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. J. Hum. Genet. 46, 182–187 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Vivanco, I. et al. Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell 11, 555–569 (2007). This paper shows that PTEN loss leads to AKT activation and to increased JNK activity in human cancer cell lines and clinical prostate samples.

    Article  CAS  PubMed  Google Scholar 

  140. Ouyang, X. et al. Activator protein-1 transcription factors are associated with progression and recurrence of prostate cancer. Cancer Res. 68, 2132–2144 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Konishi, N. et al. Function of JunB in transient amplifying cell senescence and progression of human prostate cancer. Clin. Cancer Res. 14, 4408–4416 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Liu, J. et al. Analysis of Drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer. Science 323, 1218–1222 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Li, J. et al. Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nature Genet. 31, 133–134 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Yu, W. et al. A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene 26, 1178–1187 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Iyoda, K. et al. Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 97, 3017–3026 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Elenitoba-Johnson, K. S. et al. Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc. Natl Acad. Sci. USA 100, 7259–7264 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Greenberg, A. K. et al. Selective p38 activation in human non-small cell lung cancer. Am. J. Respir. Cell. Mol. Biol. 26, 558–564 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Esteva, F. J. et al. Prognostic significance of phosphorylated p38 mitogen-activated protein kinase and HER-2 expression in lymph node-positive breast carcinoma. Cancer 100, 499–506 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Pomerance, M., Quillard, J., Chantoux, F., Young, J. & Blondeau, J. P. High-level expression, activation, and subcellular localization of p38-MAP kinase in thyroid neoplasms. J. Pathol. 209, 298–306 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. Mayer, R. J. & Callahan, J. F. p38 MAP kinase inhibitors: a future therapy for inflammatory diseases. Drug Discovery Today 3, 49–54 (2006).

    Article  Google Scholar 

  151. Reinhardt, H. C., Aslanian, A. S., Lees, J. A. & Yaffe, M. B. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11, 175–189 (2007). This paper shows that the p38-activated kinase MK2 is important for the survival of cancer cells treated with chemotherapeutic drugs that induce DNA damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vaidya, A. A., Sharma, M. B. & Kale, V. P. Suppression of p38-stress kinase sensitizes quiescent leukemic cells to anti-mitotic drugs by inducing proliferative responses in them. Cancer Biol. Ther. 7, 1232–1240 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Olson, J. M. & Hallahan, A. R. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol. Med. 10, 125–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Bogoyevitch, M. A. & Arthur, P. G. Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim. Biophys. Acta 1784, 76–93 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Salh, B. c-Jun N-terminal kinases as potential therapeutic targets. Expert Opin. Ther. Targets. 11, 1339–1353 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Yao, K. et al. A selective small-molecule inhibitor of c-Jun N-terminal kinase 1. FEBS Lett. 583, 2208–2212 (2009).

    Article  CAS  PubMed  Google Scholar 

  157. Borsello, T. et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Med. 9, 1180–1186 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Stebbins, J. L. et al. Identification of a new JNK inhibitor targeting the JNK–JIP interaction site. Proc. Natl Acad. Sci. USA 105, 16809–16813 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Adams, R. H. et al. Essential role of p38α MAP kinase in placental but not embryonic cardiovascular development. Mol. Cell 6, 109–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Mudgett, J. S. et al. Essential role for p38α mitogen-activated protein kinase in placental angiogenesis. Proc. Natl Acad. Sci. USA 97, 10454–10459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tamura, K. et al. Requirement for p38α in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 102, 221–231 (2000).

    Article  CAS  PubMed  Google Scholar 

  163. Sabio, G. et al. p38γ regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 24, 1134–1145 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Sumara, G. et al. Regulation of PKD by the MAPK p38d in insulin secretion and glucose homeostasis. Cell 136, 235–248 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to L. Bakiri, L. Hui, N. Kraut, K. Sabapathy and M. Thomsen for critical comments on the manuscript and A. Bozec for help with the figures. Work in the laboratory of E.F.W. and A.R.N. is funded by the Centro Nacional de Investigaciones Oncológicas. A.R.N. is also supported by grants from the Spanish Ministerio de Ciencia e Innovación (MICINN) (BFU2007-60575), Fundación La Caixa, MICINN/ISCIII-RTICC RD06/0020/0083 and the European Commission FP7 programme grant 'INFLA-CARE' (EC contract number 223151), and E.F.W. is also supported by the consortium CELLS INTO ORGANS of the EC-FP7 and the BBVA-Foundation.

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Erwin F. Wagner's homepage

Ángel R. Nebreda's homepage

Glossary

AP1

A dimeric transcription factor complex that contains members of the Jun, Fos, Atf and Maf protein families. Expression of these 'immediate early genes' is often low or undetectable in quiescent cells, but activated in minutes following extracellular stimulation, such as the addition of a growth factor or ultraviolet irrradiation and other stresses.

Concanavalin A mouse model

This hepatitis model requires intravenous injection of the lectin concanavalin A and is dependent on T cells and inflammatory cytokines, such as TNFα It recapitulates aspects of viral and autoimmune hepatitis in humans.

DEN–phenobarbital protocol

A fully established and widely used model for liver cancer development in mice. In several studies only the carcinogen DEN (diethylnitrosamine) is applied to young mice without tumour promotion, whereas the classical protocol depends on two-stage carcinogenesis with DEN being applied as the initiator and phenobarbital as the promoter of liver carcinogenesis.

DMBA–TPA protocol

A widely applied and fully established two-stage skin carcinogenesis protocol that depends on tumour initiation with DMBA (7,12-dimethylbenz(a)anthracene) and promotion with TPA (12-O-tetradecanoylphorbol-13-acetate).

Apcmin mice

Mice carrying a mutation in the Apc tumour suppressor gene, which is thought to initiate intestinal tumorigenesis. Mutation of Apc leads to increased β-catenin-mediated transcription of proliferation-promoting genes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, E., Nebreda, Á. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9, 537–549 (2009). https://doi.org/10.1038/nrc2694

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2694

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing